1. Field of the Invention
The present application relates to a process for the selective N-sulfonylation of oxindoles, in particular a process for the N-sulfonylation of 3-triazinyloxindoles, and also to the use thereof as intermediates for the synthesis of fine chemicals and of active ingredients in the field of agriculture.
2. Description of Related Art
Moreover, the present application relates to N-sulfonyl-substituted 3-triazinyloxindoles and their use as intermediates for the synthesis of fine chemicals in the field of agriculture.
The processes for the N-sulfonylation of oxindoles known from the prior art are often not aimed at carrying out the reaction on an industrial scale. Accordingly, the use of the activating agents used for processes known hitherto, in particular the bases used for the deprotonation, are not suitable for carrying out the reaction on an industrial scale.
Moreover, the prior art does not disclose a general principle for the as far as possible selective preparation of N-sulfonyl-substituted oxindoles. It is known that reactions for the sulfonylation of oxindoles can proceed unselectively depending on the reaction conditions, where (instead of the desired N-sulfonylated oxindole), an O-sulfonylated product or a disulfonylated, i.e. sulfonylated on the oxygen and on the nitrogen, product can be formed.
Examples for demonstrating the relatively low selectivity of the sulfonylation of oxindoles can be found e.g. in Synthetic Commun. (1992) 22, 2987 or Org. Biomol. Chem. (2009) 7, 3413. In this connection, it is assumed that the likelihood of the formation of O-sulfonylated products is increased particularly in the case of oxindoles in which at least one of the substituents in the 3 position is hydrogen.
Deprotonation
The deprotonation of the oxindole in the 1 position that precedes the sulfonylation is presumably an important prerequisite for the selectivity of the sulfonylation. The substitution of the oxindole backbone moreover, but especially the presence of a base serving as activating agent, can likewise be decisive for the progress of the sulfonylation.
It is known that hydrogen on heteroatoms in aliphatic, aromatic or heteroaromatic compounds can be replaced by functional substituents, such as e.g. a sulfonyl group. It is likewise known that N-unsubstituted or N-monosubstituted amides react with sulfonylation reagents such as sulfonyl chlorides in the presence of bases to give N-sulfonylamides.
Whereas amide sulfonylations can also be carried out with weak bases, such as e.g. pyridine or triethylamine, it is generally known (Blakemore, P. R.: N-Sulfonylation of Amides, Science of Synthesis, 21 (2005), p. 879), that the reaction is in most cases more successful if the deprotonation of the substrate is carried out with strong bases such as e.g. sodium hydride, butyllithium or lithium hexamethyldisilazane, in which case the deprotonation precedes the addition of the sulfonylation reagent to the nucleophilic amide anion that is produced on account of the deprotonation.
N-Sulfonyl-Substituted Oxindoles
Compounds which can be prepared in the manner specified in the preceding paragraph are e.g. optionally substituted oxindoles (1,3-dihydro-2H-indol-2-ones), in which, in the 1 position, hydrogen has been replaced by a sulfonyl substituent. These compounds are referred to as N-sulfonyl-substituted oxindoles.
Phenyl-Substituted Oxindoles
A subgroup of the N-sulfonyl-substituted oxindoles are those oxindoles which carry a phenyl substituent in the 3 position. Examples of syntheses of such compounds in which, in the 1 position, hydrogen has been replaced by a sulfonyl substituent can be found e.g. in FR 2714378, US 1997/5594023, US 2004/180878, US 2005/70718, WO 2006/110917, WO 2006/072458, WO 2006/100080, WO 2006/100081, WO 2006/100082, WO 2008/107399, WO 2008/025735, US 2008/318923, US 2009/318406, and in Bioorg. Med. Chem. Lett. (1998), 8, 175; Chem. Commun. (2009) 26, 3955.
A common feature of the reactions disclosed in the aforementioned prior art is that strong bases, such as sodium hydride or potassium tert-butylate, are used for the sulfonylation. However, these strong bases are sensitive to water and can therefore not be recovered undecomposed following an aqueous work-up. Moreover, these strong bases disadvantageously bring about the formation of equimolar amounts of elemental hydrogen and are therefore expensive. Consequently, the industrial use of these bases is not advantageous.
There are barely any examples in the prior art for the use of the weak base triethylamine for the sulfonylation of an oxindole which is substituted in the 3 position with phenyl and also imidazol-1-yl (European Journal of Medicinal Chemistry (1981), 16, 373). The chemical yield of the sulfonylation reaction from the aforementioned publication, however, is only 12% and is therefore unsuitable for use on an industrial scale (Example 1, variant F).
Hetaryl-Substituted Oxindoles
Oxindoles which carry a hetaryl substituent in the 3 position form a further subgroup of the N-sulfonyl-substituted oxindoles. Examples of reactions for obtaining N-sulfonyl-substituted oxindoles with a 6-ring hetaryl substituent in the 3 position, in which hydrogen in the 1 position is replaced by a sulfonyl substituent, are 3-(3-pyridyl)-substituted oxindoles (US 2005/70718, WO 2009/083559, WO 2008/80970), or 3-(3,5-pyrimidyl)-substituted oxindoles (US 2005/70718). However, it is also a common feature of the reactions disclosed in the aforementioned prior art that, for the sulfonylation, strong bases such as sodium hydride or potassium tert-butylate are used, the use of which on an industrial scale has the disadvantages described above.
N-Sulfonylation of Phenyl-Substituted Oxindoles with Sodium Carbonate
Scheme 1 summarizes a known process (J. Chem. Soc. (1957), 4789-4798) for the N-sulfonylation of an oxindole which carries a phenyl ring in the 3 position as a substituent. This process is notable for the fact that it is carried out not as in the reactions disclosed in the aforementioned prior art using strong bases such as sodium hydride or potassium tert-butylate, but with sodium carbonate as base in water/acetone. For the described reaction of 3-phenyloxindole A with 4-methylbenzenesulfonyl chloride, as product B 3-phenyl-1-toluene-p-sulfonyloxindole is given and a yield of 41% is specified.

For comparison purposes, the reaction was reworked under the conditions described in J. Chem. Soc. (1957), 4789-4798 on page 4796 for the reaction of 3-phenyloxindole, using 4-methylbenzenesulfonyl chloride as sulfonylating agent, and sodium carbonate in water/acetone as base. Following product isolation, it was established by NMR analysis that in this reaction, the main component formed is not the N-sulfonylated product B, as postulated, but the O-sulfonylated product C (Example 11). Consequently, the process known from J. Chem. Soc. (1957), 4789 is not suitable for the preparation of N-sulfonyl-substituted 3-(phenyl)oxindoles.
N-Sulfonyl-Substituted 3-Triazinyloxindoles
N-Sulfonyl-substituted 3-triazinyloxindoles, which form a further subgroup of the N-sulfonyl-substituted oxindoles hetaryl-substituted in the 3 position are not described in the prior art. This is also true for processes for the preparation of N-sulfonyl-substituted 3-triazinyloxindoles.
One group of the N-sulfonyl-substituted 3-triazinyloxindoles that is particularly important from an economical point of view is those compounds which carry, as substituents of the N-sulfonyl group, completely or partially fluorine-substituted C1-C6 alkyl groups, in particular difluoromethyl and trifluoromethyl, or (C3-C7)-cycloalkyl groups. These compounds are suitable as active ingredients in pharmacy or agriculture or as intermediates for producing fine chemicals and active ingredients in the field of pharmacy or agriculture.
Again for comparison purposes, the conditions described in J. Chem. Soc. (1957), 4789-4798, on page 4796, were also applied to a 3-(triazinyl)oxindole during the reaction with 4-methylbenzenesulfonyl chloride. However, it was detected, by UV absorption and NMR analysis, that, likewise, it was not the N-sulfonylated product which is formed, but the O-sulfonylated product (Example 13). Consequently, the described process is likewise unsuitable for preparing N-sulfonyl-substituted 3-triazinyloxindoles.
N-Sulfonylation of Phenyl-Substituted Oxindoles with Sodium Hydride
US 2009/0318406 discloses a process for the sulfonylation in the 1 position of an oxindole which carries, as substituents in the 3 position, a substituted phenyl ring or a substituted piperazine ring. The process is carried out using sodium hydride as base in tetrahydrofuran as solvent at 0° C.
Again for comparison purposes, the conditions described in US 2009/0318406 on page 19, paragraph 243, were also applied to the reaction of a 3-triazinyloxindole with difluoromethanesulfonyl chloride. However, it was established that after a reaction time of 12 hours, virtually no conversion to the desired product had taken place (Example 1, variant D). Consequently, the process described in US 2009/0318406 is not suitable for preparing N-sulfonyl-substituted 3-triazinyloxindoles on an industrial scale, at least if difluoromethanesulfonyl chloride is used as sulfonylating agent.
N-Sulfonylation of Phenyl-Substituted Oxindoles with Potassium Tert-Butylate
US 2010/69384 discloses a process for the sulfonylation in the 1 position of an oxindole which carries, as substituents in the 3 position, a substituted phenyl ring and a methyl group. The process is carried out using potassium tert-butylate as base in tetrahydrofuran as solvent at −30° C.
Again for comparison purposes, the conditions described in US 2010/69384 on page 15, Example 7A, were also applied to the reaction of a 3-(triazinyl)oxindole with difluoromethanesulfonyl chloride. However, it was established that, after a reaction time of 12 hours, virtually no conversion to the desired product had taken place (Example 1, variant E). Consequently, the process described in US 2010/69384 is also not suitable for preparing N-sulfonyl-substituted 3-triazinyloxindoles, at least if difluoromethanesulfonyl chloride is used as sulfonylating agent.
The process for the sulfonylation of an oxindole substituted in the 3 position with phenyl and also imidazol-1-yl disclosed in European Journal of Medicinal Chemistry (1981), 16, 373 has already been discussed. The process is notable for the use of triethylamine as base with dichloromethane as solvent.
Again for comparison purposes, the conditions described in Journal of Medicinal Chemistry (1981), 16, 373 were also applied to the reaction of a 3-(triazinyl)oxindole with difluoromethanesulfonyl chloride. However, it was established that, after a reaction time of 3 hours and being left to stand for 15 hours, virtually no conversion to the desired product had taken place (Example 1, variant F). Consequently, the described process is not suitable for preparing N-sulfonyl-substituted 3-triazinyloxindoles, at least if difluoromethanesulfonyl chloride is used as sulfonylating agent.